This invention is in the area of synthetic nucleosides, and is specifically directed to 1,3-oxaselenolane nucleosides and their pharmaceutical uses, compositions, and method of preparation.
In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system, and that almost without exception led to death. In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV).
In 1985, it was reported that the synthetic nucleoside 3'-azido-3'-deoxythymidine (AZT) inhibits the replication of human immunodeficiency virus. Since then, a number of other synthetic nucleosides, including 2',3'-dideoxyinosine (DDI), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxy-2',3'-didehydrothymidine (D4T), and (1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-me thanol succinate ("159U89"), have been proven to be effective against HIV. In general, after cellular phosphorylation to the 5'-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3'-hydroxyl group. They can also or alternatively inhibit the viral enzyme reverse transcriptase or DNA polymerase.
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that substitute a heteroatom for the carbon atom at the 3'-position of the nucleoside. Norbeck, et al., disclosed that (.+-.)-1-[(2.beta.,4.beta.)-2-(hycroxymethyl)-4-dioxolanyl]thymine (referred to as (.+-.)-dioxolane-T) exhibits a modest activity against HIV (EC.sub.50 of 20 .mu.M in ATH8 cells), and is not toxic to uninfected control cells at a concentration of 200 .mu.M. Tetrahedron Letters 30 (46), 6246, (1989). European Patent Application Publication No. 0 337 713 and U.S. Pat. No. 5,041,449, assigned to BioChem Pharma, Inc., disclose racemic 2-substituted-4-substituted-1,3-dioxolanes that exhibit antiviral activity. Published PCT applications PCT/US91/09124 and PCT/US93/08044 disclose purified .beta.-D-1,3-dioxolanyl nucleosides for the treatment of HIV infection. PCT discloses the use of purified .beta.-D-1,3-dioxolanyl nucleosides for the treatment of HBV infection.
PCT/US95/11464 discloses that (-)-(2S,4S)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl)cytosine is useful in the treatment of tumors and other abnormal cell proliferation.
U.S. Pat. No. 5,047,407 and European Patent Application Publication No. 0 382 526, both to BioChem Pharma, Inc., disclose that a number of racemic 2-substituted-5-substituted-1,3-oxathiolane nucleosides have antiviral activity, and specifically report that the racemic mixture of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (referred to below as BCH-189) has approximately the same activity against HIV as AZT, with less toxicity. U. S. Pat. No. 5,539,116 to Liotta, et al., directed to the (-)-enantiomer of BCH-189, known as 3TC, is now sold commercially for the treatment of HIV in humans in the United States.
It has also been disclosed that cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane ("FTC") has potent HIV activity. Schinazi, et al., "Selective Inhibition of Human Immunodeficiency viruses by Racemates and Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-yl]Cytosine" Antimicrobial Agents and Chemotherapy, November 1992, page 2423-2431. See also U.S. Pat. No. 5,210,085; U.S. Pat. No. 5,204,466, WO 91/11186, and WO 92/14743.
Another virus that causes a serious human health problem is the hepatitis B virus (referred to below as "HBV"). HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown. It is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed.
Patients typically recover from acute hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
In western industrialized coutrines, high risk groups for HBV infection include those in contact with HBV carriers or their blood samples. The epidemiology of HBV is very similar to that of acquired immune deficiency syndrome, which accounts for why HBV infection is common among patients with AIDS or AIDS related complex. However, HBV is more contagious than HIV.
Both FTC and 3TC exhibit activity against HBV. See Furman, et al., "The Anti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profiles of the (-) and (+) Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-oxathiolane-5-yl]-Cytosine" Antimicrobial Agents and Chemotherapy, l December 1992, page 2686-2692; and Cheng, et al., Journal of Biological Chemistry, Volume 267(20), 13938-13942 (1992).
A human serum-derived vaccine has been developed to immunize patients against HBV. However, more recently, vaccines have also been produced through genetic engineering and are currently used widely. Unfortunately, vaccines cannot help those already infected with HBV. Daily treatment with a-interferon, a genetically engineered protein, has also shown promise, but this therapy is only successful in about one third of treated patients. Further, interferon cannot be given orally.
Since 1,3-dioxolane and 1,3-oxathiolane nucleosides have exhibited promising antiviral and anticancer activities, it was of interest to synthesize an isosteric class of compounds, 1,3-oxaselenolane nucleosides in search of biologically interesting nucleosides. Despite their structural similarity to the 3'-heteroatom substituted nucleosides, the synthesis of 1,3-oxaselenolane nucleosides has been elusive as the construction of the oxaselenolane ring is difficult. For this reason, it appears that 1,3-oxaselenolane nucleosides have never been reported.
In light of the fact that acquired immune deficiency syndrome, AIDS-related complex, and hepatitis B virus have reached epidemic levels worldwide, and have tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat these diseases.
Therefore, it is an object of the present invention to provide a method and composition for the treatment of human patients infected with HIV.
It is another object of the present invention to provide a method and composition for the treatment of human patients or other host animals infected with HBV.
It is a further object of the invention to provide a method for the synthesis of 1,3-oxaselenolanyl nucleosides.
It is a still further object of the invention to provide 1,3-oxaselenolanyl nucleosides and pharmaceutical compositions that include 1,3-oxaselenolanyl nucleosides.